Elevated concentrations of monocyte derived cytokines in synovial fluid of children with enthesitis related arthritis and polyarticular types of juvenile idiopathic arthritis

Abstract

OBJECTIVE: Cytokines are the major mediators of joint damage in chronic arthritis. Data on synovial fluid (SF) cytokine concentrations in patients with juvenile idiopathic arthritis (JIA), especially enthesitis related arthritis (ERA), are limited. We measured levels of different monocyte derived cytokines, T cell derived cytokines, and a proinflammatory chemokine in SF specimens from children with ERA or polyarticular (Poly) rheumatoid factor (RF)-negative JIA. METHODS: Macrophage products [tumor necrosis factor-a (TNF-a), interleukin 1ss (IL-1ss), IL-6, IL-12p40)], T lymphocyte products [IL-2, IL-4, interferon-g (IFN-g)], and a proinflammatory chemokine (IL-8) were assayed using ELISA in SF specimens from 53 patients with JIA [ERA 34, polyarticular RF-negative 19] and 40 patients with rheumatoid arthritis (RA). RESULTS: In the ERA group, median SF cytokine levels were higher compared to RA (all values are pg/ml): IL-1ss [< 15.6 (< 15.6-213) vs < 15.6 (< 15.6-41); p < 0.01], IL-12p40 [236 (< 15.6-1714) vs 21 (< 15.6-520); p < 0.0001], and IL-6 [1139 (< 4.6-2187) vs 835 (< 4.6-875); p < 0.0001]. TNF-a and IFN-g levels were similar to RA. IL-8 levels were significantly less than RA (p < 0.0001). The median levels of IL-1ss [39.4 (< 15.6-558) vs < 15.6 (< 15.6-41); p < 0.0001] and IL-12p40 [209 (< 15.6-849) vs 21 (< 15.6-520); p < 0.0001] were higher in patients with Poly-JIA compared to RA. TNF-a, IL-6, and IL-8 levels in Poly-JIA were comparable to RA. IL-2 and IL-4 were not detectable in any patient with JIA. Cytokine profile comparison between the 2 subsets revealed that the median IL-6 [1139 (< 4.6-2187) vs 790 (17.4-2119); p < 0.01] and IFN-g levels [235 (< 4.6-600) vs < 4.6 (< 4.6-412); p < 0.0001] were higher in ERA than in Poly-JIA. In contrast, median IL-8 levels were higher in Poly-JIA [200 (3.8-200)] compared to ERA [74.6 (4-200); p < 0.001]. However, there was no difference in levels of TNF-a, IL-1ss, and IL-12p40 between patients with these 2 subtypes of JIA. CONCLUSION: SF levels of IL-1ss and IL-12p40 are increased in both Poly-JIA and ERA as compared to RA. IL-6 levels were higher in ERA compared to RA. Levels of TNF-a were comparable to RA in both Poly-JIA and ERA. This suggests that joint inflammation in JIA is mediated predominantly by monocytes. In ERA the levels of IL-6 and IFN-g are higher than in Poly-JIA. The increase in IFN-g in children with ERA with undetectable IL-4 suggests a Th1-dominant immune response in this disease subset.